Influence of Exercise Capacity on Tolerance of Ischemia Reperfusion or Pressure Overload

Background: Ischemia/reperfusion (I/R) and pressure overload (PO) represent potentially detrimental stresses to the heart. Exercise capacity is considered protective against cardiovascular disease improving survival. We tested how the intrinsic (i.e., genetically determined) exercise capacity influences stress resistance. We used the model of high (HCR) or low (LCR) exercise capacity rats and tested for tolerance to cardiac stress.

Methods: Rats were bred for 36 generations for high or low intrinsic exercise capacity. PO was induced in three week old HCR or LCR by transverse aortic constriction (TAC). Cardiac function was assessed echocardiographically at 2, 10, and 18 weeks and survival time was recorded. I/R was assessed using ex vivo cardiac perfusion in 18 weeks old HCR and LCR.

Results: Phenotypically, HCR were leaner (247 ± 13 vs. 321 ± 7 g), had higher spontaneous exercise capacity (39.3 ± 0.3 vs. 23.5 ± 0.2 m/min), and LCR displayed signs of the metabolic syndrome. There was no difference in cardiac function. PO led to marked hypertrophy in both HCR and LCR already at 2 weeks (LVTWT,d: HCR 2.87 ± 0.31 vs. HCR-TAC 3.8 ± 0.17 and LCR 2.67 ± 0.14 vs. LCR-TAC 4.12 ± 0.06). After 10 weeks of PO, diastolic function was impaired in both HCR and LCR. However, fractional shortening was significantly worse in HCR than in LCR at 10 weeks (FS: HCR-TAC 36.7 ± 2.4%, LCR-TAC 50.2 ± 4.0%) and thereafter (HCR-TAC 33.4 ± 3.0 vs. LCR-TAC 40.9 ± 1.8%; p = 0.03). In addition, survival was significantly lower in HCR with PO (mean survival time: HCR 16.0 ± 1.6 vs. LCR 22.4 ± 1.7 weeks; p = 0.03).

Recovery after I/R in isolated working hearts was also worse in HCR than in LCR (HCR 41.6 ± 4.8% of baseline LCR 56.4 ± 7.5%). Furthermore, the number of hearts not recovering was higher in HCR (33%) than in LCR (16%; p < 0.05). HCR were metabolically characterized by high glucose and oleate oxidation displaying reduced efficacy (22.4 ± 4.1 vs. 16.2 ± 1.8 µmol ATP/W).

Conclusion: The genetic predisposition for high exercise capacity may not offer cardioprotection during PO or I/R. If relevant in humans, the correlation between high exercise capacity and low CV disease may then be primarily due to the trained part of exercise capacity.